Arachidonic Acid Pathways and Male Fertility: A Systematic Review

Arachidonic acid (AA) is a polyunsaturated fatty acid that is involved in male fertility. Human seminal fluid contains different prostaglandins: PGE (PGE1 and PGE2), PGF2α, and their specific 19-hydroxy derivatives, 18,19-dehydro derivatives of PGE1 and PGE2. The objective of this study is to synthesize the available literature of in vivo animal studies and human clinical trials on the association between the AA pathway and male fertility. PGE is significantly decreased in the semen of infertile men, suggesting the potential for exploitation of PGE agonists to improve male fertility. Indeed, ibuprofen can affect male fertility by promoting alterations in sperm function and standard semen parameters. The results showed that targeting the AA pathways could be an attractive strategy for the treatment of male fertility.


Introduction
Arachidonic acid (AA) is a polyunsaturated fatty acid released by the activation of phospholipase A 2 (PLA 2 ) that is transformed into a series of metabolites by different enzymes. Reactive oxygen species (ROS) and cytokines can also activate PLA 2 . The most known pathway of AA is the cyclooxygenase (COX) pathway which is responsible for the production of prostaglandins (PGs) and thromboxane (TX). The lipoxygenases (LOs) pathway brings to the production of both, leukotrienes (LT) and anti-inflammatory lipoxins (LXs) (Figure 1) [1]. Cytochrome P450 (CYP) enzyme is another pathway of AA transformation that gives rise to epoxyeicosatrienoic acids (EETs), and 20-hydroxyeicosatetraenoic acid (20-HETE). 5-, 8-, 12-, and 15-lipoxygenases (15-LOX) produce hydroperoxyeicosatetraenoic acid (HPETE).
Von Euler in the earliest 1930s was the first to report the presence of PGs in the seminal plasma. They were thought to originate from the prostate gland, and for this reason they were named prostaglandins [2]. The PGs present in human semen are the PGE (PGE 1 and PGE 2 ), PGF 2α , and their specific 19-hydroxy derivatives, 18,19-dehydro derivatives of PGE 1 and PGE 2 . PGE 2 and 19-hydroxy PGE  are the main PGs present in semen [3,4]. PGs content in fertile men's ejaculate is 1 mg [5]. Seminal vesicles are the main source of PGs in human semen [6], with additional contributions from epididymis, vas deferens, and testes [7]. Ollero et al. reported that high levels of AA are related to defective human spermatozoa [8,9]. In line with these findings, other studies demonstrated that the exposure of human spermatozoa to AA and other PUFAs can cause DNA spermatozoa damage [10]. Cosentino et al. showed that the levels of PGE 2 are 15 to 25 times higher in the lumen of ram cauda epididymidis in respect to rete testis. In washed sperm recovered from the vas deferens of rams PGE 2 increases the sperm cyclic adenosine monophosphate (cAMP) [7]. It is still unclear whether this is a receptor-mediated process. Interestingly Hedqyist et al., reported that PGs can also mediate the uptake of receptor-mediated process. Interestingly Hedqyist et al., reported that PGs can also mediate the uptake of Ca 2+ into the cell [11]. PGE can decrease calcium uptake in spermatozoa through the increase of intercellular cAMP concentration [12]. Another potential role of PGs can be the sperm transport through the distal epididymidis and vas deferens [13]. PGD2 can regulate epithelial apoptosis [14]. Lipocalin type prostaglandin D-synthase (L-PGDS) that is responsible for the production of prostaglandin D2 (PGD2) is abundant in the seminal fluid of fertile men, and is significantly decreased in the semen of oligozoospermic men [15]. The role of seminal L-PGDS is to provide retinoids in seminiferous tubules, as well as the maturing spermatozoa in the epididymis [16]. L-PGDS is found either in seminal plasma, or on sperm surface, and L-PGDS levels were significantly reduced in oligozoospermic patients. Chen et al. reported that L-PGDS may act as the main protein in improving the progressive motility of sperm by increasing either the capacity of sperm to bind to eggs or to agglutinate, or by increasing the percentage of motile sperm [17]. In addition, COX-2 was found to be implicated in testicular inflammation related to idiopathic infertility in biopsies of men with impaired spermatogenesis [18]. Alteration of PGs synthesis in the testis is another potential reason for idiopathic male fertility [19]. However, both COX-1, and COX-2 isoforms were not found in normal human testes [20]. Schell et al. demonstrated that testicular PGD synthases are expressed in normal and pathological situations [21]. There are few reports on the role of 15-Hydroperoxyeicosatetraenoic acid  in sperm function and membrane integrity [22]. 15(S)-lipooxygenase was figured out to be involved in sperm acrosome reaction [23,24]. The aim of this study is to synthesize the existing evidence on the implication of PGs in male fertility.  Arachidonic acid mediators or enzymes that are marked in red are known to be involved in male fertility. Abbreviations: arachidonic acid (AA), phospholipase A 2 (PLA 2 ), cyclooxygenase (COX), prostaglandin G 2 (PGG 2 ), prostaglandin H 2 (PGH 2 ), thromboxane synthase (TXS), thromboxane A 2 (TXA 2 ), thromboxane B 2 (TXB 2 ), prostaglandin E synthase (PGES), prostaglandin E 2 (PGE 2 ), prostaglandin D synthase (PGDS), prostaglandin D 2 (PGD 2 ), 15-deoxy-D12,14-prostaglandin J 2 (15d-PGJ 2 ), prostaglandin F synthase (PGFS), prostaglandin F 2α (PGF 2α ), 15-keto Prostaglandin F 2α (15-keto PGF 2α ), prostaglandin I synthase (PGIS), prostacyclin (PGI 2 ), 6-keto Prostaglandin F 1α (6-keto PGF 1α ).

Research Methods and Reporting
This systematic review followed the preferred reporting items for systematic reviews (PRISMA) guidelines.

Study Design
We conducted a systematic review to report all the findings of in vivo animal studies and human clinical trials on the association between AA pathways and male fertility.

Eligibility Criteria
The eligibility criteria for inclusion were: All Randomized Controlled Trials (RCTs), or observational studies (cohort or case control design) reporting the association of the AA pathway with male fertility. We excluded reviews, and studies on the association of AA pathways with female fertility. The literature search was not restricted by the year of publication.

Literature Search, Information Sources and Selection of Articles
We collected all the relevant data that conformed to the eligibility criteria on the role of the AA pathway in male fertility. We searched in Pubmed, Scopus, Medline, and Embase databases all studies reporting the association between arachidonic acid mediators and male fertility using the following text words; "arachidonic acid and male fertility"; "prostaglandin and male fertility"; "thromboxane and male fertility"; "leukotriene and male fertility";"lipoxin and male fertility"; "5-lipoxygenase and male fertility"; "12-lipoxygenase and male fertility"; "15-lipoxygenase and male fertility"; "pro-resolving lipid mediators and male fertility"; "cytochrome P450 epoxygenase pathway and male fertility". Only studies that fulfilled the eligibility criteria were included.

Data Synthesis
Only 68 articles out of 456 identified articles, were included in this systematic review. Duplicates articles, studies that did not report the association of AA pathways with male fertility, reviews, and original articles reporting AA pathways and female fertility were excluded.
The findings were classified in three tables, reporting findings from animal studies, human studies, and studies on the potential effects of NSAIDs in seminal PGs. One article was placed in more than one table because it contains data from animal study, and data on the effects of NSAIDs (flurbiprofen, indomethacin) in seminal prostaglandins.

Results
A schematic diagram of the literature search procedure is shown in Figure 2.

Findings from Animal Studies
As shown in Table 1, we identified a total of 17 studies carried out in different animal models (male rats, mice, dromedary camels, ram/bulls). Different AA mediators or enzymes involved in the AA pathway were assessed (AA, PGE 1 , PGE 2 , PGF 2α , sPLA 2 , PGDS).
A study conducted in dromedary camels showed that sPLA 2 is a fertility-associated biomarker in seminal plasma and serum. Group VIA Phospholipase A 2 (iPLA 2β ) has an important role in spermatozoa [25]. Data showed also that prostaglandin D synthase (lipocalcin-type) is negatively related to camels' fertility [26]. Fouchécourt et al. showed that prostaglandin D synthase had a high capacity to bind to testosterone and its levels were increased in animals with normal or high fertility [27].

Findings from Animal Studies
As shown in Table 1, we identified a total of 17 studies carried out in different animal models (male rats, mice, dromedary camels, ram/bulls). Different AA mediators or enzymes involved in the AA pathway were assessed (AA, PGE1, PGE2, PGF2α, sPLA2, PGDS).
A study conducted in dromedary camels showed that sPLA2 is a fertility-associated biomarker in seminal plasma and serum. Group VIA Phospholipase A2 (iPLA2β) has an important role in spermatozoa [25]. Data showed also that prostaglandin D synthase (lipocalcin-type) is negatively related to camels' fertility [26]. Fouchécourt et al. showed that prostaglandin D synthase had a high capacity to bind to testosterone and its levels were increased in animals with normal or high fertility [27].
AA is one of the main components of testicular membranes in mice [29]. In addition, AA was found to be not as effective as DHA in restoring fertility and sperm count [30]. The higher absolute amount of n-3 and n-6 PUFA are more important for reproduction than the n-6/n-3 FA ratios [31].
PGE2 is the main PG found in the seminal fluid [32]. Different studies reported that intravenous or intraventricular administration of low dose PGs of the E series in male rats can enhance the production of LH [33,34]. Interestingly intratesticular injection of 2.5 mg/kg of PGEl, or PGE2 affects the capacity of fertilizing of epididymal spermatozoa in male rats. Instead, no effects on male rat fertility were reported for PGF2α, despite AA is one of the main components of testicular membranes in mice [29]. In addition, AA was found to be not as effective as DHA in restoring fertility and sperm count [30]. The higher absolute amount of n-3 and n-6 PUFA are more important for reproduction than the n-6/n-3 FA ratios [31]. PGE 2 is the main PG found in the seminal fluid [32]. Different studies reported that intravenous or intraventricular administration of low dose PGs of the E series in male rats can enhance the production of LH [33,34]. Interestingly intratesticular injection of 2.5 mg/kg of PGE l , or PGE 2 affects the capacity of fertilizing of epididymal spermatozoa in male rats. Instead, no effects on male rat fertility were reported for PGF 2α , despite suppressing the testis and epididymis weight [35]. Both PGs of the E series (PGE 1 and PGE 2 ) did not have any local effect on epididymal spermatozoa fertilizing capacity, despite reducing the weight of the injected testis due to blood flow restriction at the site of application. Considering that PGs suppress steroidogenesis by lowering the plasma levels of androgens, the incapacity of PGs to affect the fertilizing capacity of spermatozoa in both injected and contralateral sides suggests that the androgen that has been available following the treatment schedule was enough to keep the fertilizing capacity of the epididymal spermatozoa despite of the PGs site of injection [35]. However, intratesticular injection of higher doses of PGs (2.5 mg/kg) adversely affected the fertilizing ability of spermatozoa, by affecting steroidogenesis in both the injected and contralateral control testes [35]. The short-term treatment of hamsters with PGF 2α , or PGE 1 had no effect on fertilizing capacity [36,37]. Testosterone added concurrently with PGE 1 and PGE 2 maintained both the fertilizing capacity of epididymal spermatozoa, and the weight of accessory sex glands [38]. Hafiez et al. hypothesized that PGE 2 in testes can modify the effect of trophic hormones and prevent the impairment of fertility in rats [39]. The plasma levels of androgens are decreased by both PGE 2 and PGF 2α [33]. 15-Me-PGF 2α can suppress testosterone production in the testes [40].
The testicular regression observed in the injected testis (PGE 1 , PGE 2 , PGF 2α ), could be explained by the restricted blood flow through the testes following the local application of PGs [41]. The incapacity of PGs (1 mg/kg of PGE(1 and 2) and PGF 2α ) to affect the fertilizing capacity of spermatozoa in both injected and contralateral sides suggest that androgen that has been available following the treatment schedule was enough to keep the fertilizing capacity despite of the PGs site of injection. PGs can suppress steroidogenesis in the testis and this can bring to a decrease in plasma testosterone levels in intact adult male mice. 5 Kimball et al., 1978 [40] Male Rats 15-Me-PGF 2α 15-Me-PGF 2a can suppress testosterone production in testes. 6 Memon, 1973 [34] Male Rats PGE 2 , PGF 2α The testicular weight and plasma testosterone is lower in rats treated with PGE 2 , and PGF 2α. . LH increased significantly in male rats with bilateral injection of PGs. The treatment of hamsters for a short period of time with PGF 2α , or PGE 1 had no effect on fertilizing ability.

Summary of the Results Reported by Human Clinical Trials
In Table 2, we report the main findings of human clinical studies (31 studies) that were systematically reviewed.
Isidori et al. reported that PGs can be either reduced or increased in infertile men, hence either high or low levels of PGs can be harmful [42]. PGE, PGF, and 19-OH PGF, 19-OH PGE, 6-keto-PGF 1α , and PGD 2 , were detected in the semen of fertile men [5,34,43,44]. Rather unexpectedly higher levels of PGE 2 , PGF 2α , PGI 2 , and TXA 2 were observed in the seminal plasma of diabetic patients [45], considering that diabetes is known to significantly reduce fertility rates. Despite increased seminal plasma PG concentrations are associated with oligospermia and reduced sperm motility the current data did not show these sperm defects in diabetic males [45]. Different evidence reports a positive correlation between AA levels and spermatozoa [46]. Higher levels of AA were detected in the semen of eighty-two infertile men with idiopathic oligoasthenoteratozoospermia (OAT) compared to the semen of 78 fertile men [47]. A statistically significant negative correlation was revealed between the ratios of AA with docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA), and the total sperm number, morphology, and motility [47]. Hawkins states that the higher the concentrations of semen PGs, the lower the number of abnormal spermatozoa [48]. Consentino et al. reported that PGF 2α was correlated with abnormal sperm morphology. In addition, the data revealed that Zn 2+ and Ca 2+ concentration were predictors of seminal PGF 2α , instead of sperm motility, plasma testosterone, and Ca 2+ concentration which were significant predictors of seminal PGE [13]. High levels of seminal PGF 2α may be related to impaired spermatogenesis [7]. However, other evidence has shown that the semen of fertile men contains higher levels of PGs with respect to semen of infertile men [49,50]. 19-OH-PGE and PGE levels were significantly decreased in the semen of 10 infertile males [49]. In addition, it was found that PGs levels in the semen of hypogonadal men were correlated with testosterone concentration in the blood [51]. Specifically, low PGE levels have been found either in the semen of men with "idiopathic" infertility, or of men of infertile marriages where no abnormal findings were revealed, pointing to the essential role of PGE in sperm functions not assessable by standard semen analysis [52][53][54]. In line with these findings, other data showed higher levels of PGE 2 and 19-OH PGE in the seminal plasma of fertile men with respect to the seminal plasma of patients with OAT [55]. Reduced levels of PLA 2 were observed in patients with globozoospermia [56]. Isidori et al. showed that the reduced adenylcyclase and testicular androgen activity may be responsible for the negative impact of low seminal PGs levels on sperm concentration and motility [42]. Indeed, reduced sensitivity of receptors to increased titers of PGs, and DNA synthesis inhibition in testes may be responsible for the negative impact of high seminal PGs levels.
In a Swedish study, it was revealed that 19-hydroxy PGF and 19-hydroxy PGE have a significant role in sperm motility, potentially through the ATP content in spermatozoa [57]. 15-deoxy-∆12-14-PGJ 2 , a product of COX/PGD synthase, could be involved in human sub-/infertility by affecting the human peritubular cells contractility and phenotype potentially through ROS [58]. PGD 2 synthetases (PGDS) were found in the interstitial cells of men with impaired spermatogenesis [21]. Chen et al. showed that lipocalin type (L-PGDS) in seminal plasma is positively correlated with sperm motility and density [17]. F 2 -isoprostanes (F 2 -IsoPs) are produced by the oxygenation of AA, and are related to male infertility, as a marker of sperm immaturity by affecting sperm quality [59,60]. In infertile patients with varicocele, it was observed a positive correlation between F 2 -IsoPlevels and sperm immaturity [60,61]. Recently Moretti et al., assessed the cut off value of F 2 -IsoPs semen levels in fertile and infertile men, and reported that F 2 -IsoP levels above 29.96 ng/mL are potentially related to idiopathic infertility and other pathological conditions, and can serve as an index of altered sperm quality in infertile patients [62]. Instead, resolvins are AA specialized proresolving mediators, and specifically RvD1 is an indicator of seminal pathological state [63]. High levels of RvD1 are associated with changes in sperm parameters, hypothesizing that resolvins cannot defend the male fertility, in the presence of chronic inflammation. These data support the fact that diets rich in n-3 PUFA can be helpful in male infertility with an inflammatory state [63].
However other controversial studies demonstrated no correlation between seminal PGs concentration and sperm morphology, motility, concentration, and fertility [64,65]. Dorp et al. revealed no correlation between seminal PGs and spermatozoa morphology and concentration [66]. Templeton et al. reported no significant difference in semen PGE levels between fertile and infertile men [4]. These data were further confirmed by Schlegel's findings, where no decrease in the PGE concentration was detected either in the semen of fertile, and non-fertile men [67].  Higher levels of PGE 2 were observed in the seminal plasma of fertile men in respect to seminal plasma of patient with oligoteratoasthenoazoospermia (OTA), but no differences in sperm cells functions and parameters were observed. 12 Isidori

PGE, 19-OH PGE
The reduced adenylcyclase and testicular androgen activity may be responsible of the negative impact of low seminal PGs levels in sperm concentration and motility. Indeed, reduced sensitivity of receptors to increased titers of PGs, and DNA synthesis inhibition in testes may be responsible of the negative impact of high seminal PGs levels.

Potential Effects of NSAIDs in Seminal Fluid PGs
The main characteristics of the NSAIDs' role in seminal fluid PGs and male fertility that were systematically reviewed are summarized in Table 3.
Bendvold et al. showed that all PGs (PGE, PGF, 19-hydroxy-PGE, and 19-hydroxy-PGF,8α-19-hydroxy-PGF 2α , 8ß-19-hydroxy-PGF 1α ) were reduced in semen samples of six volunteers before, during and after treatment with naproxen 250 mg 3 times daily for 2 weeks [68]. Interestingly, the results showed that for maintaining normal sperm motility it is essential to have a balanced concentration ratio between 19-hydroxy-PGF and 19-hydroxy-PGE. The short treatment with naproxen did not have any impact on human fertility. The data suggest that the reduction of PGs is not secondary to the effect of naproxen on sperm characteristics [68]. However further studies need to be performed to assess the long-term effect of naproxen, or other NSAIDs on fertility and sperm characteristics (motility, morphology, density).
Other studies using Aspirin showed a significant reduction of PGE 2 and PGF 2α levels in human seminal fluid during treatment with aspirin [69], and an 80% of reduction of seminal plasma levels of PGE following treatment with 7.2 g/day of Aspirin [70]. The mechanisms responsible for controlling the concentrations of PGE 2 and PGF 2α in semen may be different [70]. The subchronic dose of aspirin (12.5 mg/kg for 30 days and 60 days) given to male rats reduced sperm mobility and density [71]. These data were confirmed in other animal models where sperm motility, morphology and seminal volume were decreased, and spermatogenesis was impaired following aspirin use [72][73][74][75][76]. In humans, moderate aspirin use reduced the motile, progressive and rapid progressive gametes percentages [77], having a negative impact on male fertility [78]. Interestingly, the fertility increased in male mice that were classified initially as sub-fertile under treatment with aspirin (50 mg/kg twice daily for a total of 12 days) [79]. Other studies did not conclude on the role of Aspirin on spermatogenesis [80].
A recent study carried out in male rats that received ibuprofen (0; 2.4; 7.2 or 14.3 mg/kg/day) showed that the pre-pubertal treatment with ibuprofen had a negative effect on sperm quality and quantity, which affects reproduction [81]. The male offspring had an accelerated sperm transit time in the epididymis, while the fertility potential was reduced in the female offspring [81]. However, Stutz et al. showed that intramuscular injection of ibuprofen 5.6 mg/kg day reduced testosterone levels, but did not modify the sperm functional activity [82]. Flurbiprofen and indomethacin did not affect male reproduction in rats [27]. However other study showed that flurbiprofen produces a small alteration in sperm head with a larger and spherical head [83]. Löscher et al. reported that chronic treatment with phenylbutazone may improve sperm quality, increase ejaculate volume, and improve sperm fertility [84].
NSAIDs (indomethacin, naproxen, acetylsalicylic acid) decreased the PGE 2 levels in seminal fluid in rats, suggesting that these compounds can be used to control male fertility [85]. The reduction of prostaglandin synthesis in male rats does not have any effect on fertility. This can be explained by the very low seminal prostaglandin levels in rats in confront to other animals [85].
Interestingly, Conte et al., showed that indomethacin improved significantly the sperm count and motility in infertile oligozoospermic patients with high levels of PGs [86]. The number of pregnancies was reduced in the groups mated with indomethacin and oxyphenbutazone treated male rats [87]. The prolonged treatment with NSAIDs did not affect rabbit male fertility. However, chronic treatment with phenylbutazone may improve sperm quality, increase ejaculate volume, and improve sperm fertility.

Discussion
Our research study included 17 studies carried out in animals, 31 studies conducted in humans, and 21 studies that reported the association between NSAIDs and seminal fluid PGs. One of the articles was inserted in both Tables 1 and 3, respectively.
Various evidence has shown that the AA pathway and its mediators are involved in male fertility. Starting from AA, studies demonstrated that AA itself can mediate the stimulatory effect of luteinizing hormone on the synthesis of testicular steroids [88,89]. PLA 2 enzyme is also a major component in sperm [90]. COX-2 is expressed in testes of infertile men, or men with impaired spermatogenesis [18].
Human seminal fluid contains different prostaglandins that originate from the seminal vesicles, and play important roles in sperm function, and motility. They can act directly on spermatozoa through the PG receptors [53,91], and have a protective role in sperm motility. In particular, 19-OH-PGE has a protective role on the sperm from immunological damage [4]. PGs can also decrease the plasma concentration of androgens.
PGE is one of the main PGs assessed in male fertility in both animal and human clinical studies, suggesting that the semen of infertile men has lower levels of PGE [53]. Based on these findings, an increase of PGE levels in men, by using PGE agonist could be an option to treat male infertility. However other contradictory studies suggest that 19-OH-PGE and PGE concentrations can vary.
Despite PGE, hematopoietic PGD 2 synthase is also expressed in patients with impaired spermatogenesis. Its levels are reduced in oligozoospermic men [92]. Analogously another PG, respectively 15d-PGJ 2 was found in patients with idiopathic infertility [93].
Targeting the AA pathway has emerged as an attractive strategy for the treatment of male fertility. Ibuprofen can affect fertility through the alteration of sperm motility, function, viability, count potentially through the reduction of PGS synthesis [57,[94][95][96].
In addition, other NSAIDs such as flurbiprofen, acetylsalicylic acid, naproxen can decrease PG levels in human semen and increase fertility [68][69][70]83]. These findings can be partially explained by Isidori et al., that high baseline levels of PGs are harmful because they reduce testicular DNA synthesis and cause down regulation of the receptors for the same PGs. Consequently, if NSAIDs are administered to subjects with too high levels of PGs, they can have a positive effect on semen quality. Indomethacin used in oligospermic men increased fertility [97], and induces alteration of endocrine system in fetal testis, together with Aspirin and Paracetamol [98]. In addition, in a mice model Indomethacin (5 mg/kg/day), decreased the fertility of mice, in contrary with lower doses of indomethacin (3 mg/kg/day) that did not have any effect in fertility [99]. Prolonged use of indomethacin (2 mg/kg twice daily for 7 days) in male rats reduced the fertility [85].
Chronic treatment (50 mg/kg twice daily for a total of 12 days) with acetylsalicylic acid in male mice [79], or treatment with naproxen (with a maximum dose of 30 mg/kg/day for 60 days) did not have any role in fertility [100]. However, interestingly, the fertility increased in male mice that were classified initially as sub-fertile under treatment with aspirin (50 mg/kg twice daily for a total of 12 days) [79].
The subchronic dose of aspirin (12.5 mg/kg for 30 days and 60 days) given to male rats changed the reproductive profile of male rats, and reduced sperm mobility and density [71]. In line with these findings, Stutz et al. confirmed that Aspirin can have a deleterious effect on seminal parameters [77].

Conclusions
To our knowledge, this is the first study reporting and evaluating all the published studies on the association of AA pathways mediators and male fertility. Of notice, most of the references are old, and only few studies have been performed recently in the field. Studies reported in this article are not homogeneous, and often report conflicting results. However, we believe that based on the promising results from either animal or human studies, it is the duty of the academic world to keep exploring the AA pathway's implication in male fertility. Considering that PGE is the main PG involved in male fertility, and its levels are decreased in the semen of infertile men, the PGE agonist, or any drug which causes an increase in seminal PGE concentration could be suggested as a potential approach to improve male fertility. In addition, we notice that there is no information on the role of leuokotrienes, or lipoxins in semen, and on the role of sperm motility, morphology, function, and fertility. Additional studies should be carried out to further explore other AA pathways mediators, or enzymes. In addition, long term effect of NSAIDs in male fertility should be further explored. Considering that COX-2 is expressed in the testes of infertile men and is implicated in testicular inflammation related to idiopathic infertility it would be interesting assessing also the role of COXIBs in male fertility.
We believe that despite some controversial results targeting the AA pathway is a promising strategy to be further explored for expanding treatment options for male infertility.